Evaluation of binding of potential ADMET/tox screened saquinavir analogues for inhibition of HIV-protease via molecular dynamics and binding free energy calculations

This study aimed to screen putative drug targets associated with biofilm formation of multidrug-resistant Acinetobacter baumannii and Pseudomonas areugenosa and prioritize carbon nano-fullerene as potential lead molecule by structure-based virtual screening. Based on the functional role, 36 and 83 genes that are involved in biofilm formation of A. baumannii and P. areugenosa respectively were selected and metabolic network was computationally constructed. The genes that lack three-dimensional structures were predicted and validated. Carbon nano-fullerene selected as lead molecule and their drug-likeliness and pharmacokinetics properties were computationally predicted. The binding potential of carbon nano-fullerene toward selected drug targets was modeled and compared with the binding of conventional drugs, doripenem, and polymyxin-B with their usual targets. The stabilities of four best-docked complexes were confirmed by molecular dynamic (MD) simulation. This study suggested that selected genes demonstrated relevant interactions in the constructed metabolic pathways. Carbon fullerene exhibited significant binding abilities to most of the prioritized targets in comparison with the binding of last-resort antibiotics and their usual target. The four best ligand–receptor interactions predicted by molecular docking revealed that stability throughout MD simulation. Notably, carbon fullerene exhibited profound binding with outer membrane protein (OmpA) and ribonuclease-HII (rnhB) of A. baumannii and 2-heptyl-4(1H)-quinolone synthase (pqsBC) and chemotaxis protein (wspA) of P. aeruginosa. Thus, the current study suggested that carbon fullerene was probably used as potential lead molecules toward selected targets of A. baumannii and P. aeruginosa and the applied aspects probably scaled up to design promising lead molecules toward these pathogens. Communicated by Ramaswamy H. Sarma.

Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies

Background Triple-negative breast cancers are defined as tumors that lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It exhibits unique clinical and pathological features, is highly aggressive, and has a relatively poor prognosis and poor clinical outcome. Objective To identify a novel drug target protein against triple-negative breast cancer (TNBC) and potential phytochemical lead molecules against novel drug targets. Methods In this study, we retrieved TNBC samples from NGS and microarray datasets in the Gene Expression Omnibus database and employed a combination of differential gene expression studies, protein-protein interaction analysis, and network topology investigation to identify the target protein. Using molecular docking and molecular dynamics simulation studies, followed by Molecular Mechanics with Generalised Born Surface Area solvation, a potential lead molecule was identified. Result The androgen receptor (AR) was found to be the target protein, and 2-hydroxynaringenin was discovered to be a possible phytochemical lead molecule to combat TNBC. Upregulated genes with LogFC > 1.25 and P-value < 0.05 from the TNBC gene expression dataset were given to STRING tool to investigate the network topology, and androgen receptor (AR) was found to be an appropriate hub gene in the protein-protein interaction network. Phytochemicals that inhibit breast cancer were retrieved from the PubChem database and virtual screening was performed using PyRx against the AR protein. Based on Lipinski’s rule and ADMET properties, molecular interaction studies were analyzed using induced fit docking, wherein significant binding interactions were displayed by 2-hydroxynaringenin. Molecular dynamics studies and MM-GBSA of AR and the 2-hydroxynaringenin complex revealed strong and stable interactions. Conclusion AR was identified as a hub protein that is highly expressed in breast cancer and 2-hydroxynaringenin efficacy of counter TNBC needs to be investigated further in vitro and in vivo.

Herein, we report the synthesis, and characterization of a new series of 1,3,4–oxadiazole and 1,2,4–triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1H NMR, 13C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b, 6d, and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 μg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 μg/mL respectively. Particularly, the prepared scaffolds 8c, 8d, and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 μg/mL against A. flavus and 6d, 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 μg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H37Rv with MICs 3.26, and 6.48 μg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H–bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME. Communicated by Ramaswamy H. Sarma

Targeting MurG enzyme in Klebsiella pneumoniae: An in silico approach to novel antimicrobial discovery

Among various matrix metalloproteinases (MMPs), MMP-12 is one of the potential targets for cancer and other diseases. However, none of the MMP-12 inhibitors has passed the clinical trials to date. Therefore, designing potential MMP-12 inhibitors as new drug molecules can provide effective therapeutic strategies for several diseases. In this study, a series of dibenzofuran and dibenzothiophene derivatives were subjected to different 2D and 3D-QSAR techniques to point out the crucial structural contributions highly influential toward the MMP-12 inhibitory activity. These techniques identified some structural attributes of these compounds that are responsible for influencing their MMP-12 inhibition. The carboxylic group may enhance proper binding with catalytic Zn2+ ion at the MMP-12 active site. Again, the i-propyl sulfonamido carboxylic acid function contributed positively toward MMP-12 inhibition. Moreover, the dibenzofuran moiety conferred stable binding at the S1′ pocket for higher MMP-12 inhibition. The steric and hydrophobic groups were found favourable near the furan ring substituted at the dibenzofuran moiety. Besides these ligand-based approaches, molecular docking and molecular dynamic (MD) simulation studies not only elucidated the importance of several aspects of these MMP-12 inhibitors while disclosing the significance of the finding of these QSAR studies and their influences toward MMP-12 inhibition. The MD simulation study also revealed stable and compact binding between such compounds at the MMP-12 active site. Therefore, the findings of these validated ligand-based and structure-based molecular modeling studies can aid the development of selective and potent lead molecules that can be used for the treatment of MMP-12-associated diseases. Communicated by Ramaswamy H. Sarma

Triple-negative breast cancers (TNBC) are defined as tumors that lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It exhibits unique clinical and pathological features, demonstrates high aggressiveness, and has a relatively poor prognosis and clinical outcome. To identify a novel drug target protein against TNBC and potential phytochemical lead molecules against the identified target. In this study, we retrieved TNBC samples from NGS and microarray datasets in the Gene Expression Omnibus database. We employed a combination of differential gene expression studies, protein-protein interaction analysis, and network topology investigation to identify the target protein. Additionally, the molecular docking and molecular dynamics (MD) simulation studies followed by Molecular Mechanics with Generalised Born Surface Area salvation was used to identify potential lead molecule. The upregulated genes with LogFC > 1.25 and P-value < 0.05 from the TNBC gene expression dataset were identified. Androgen receptor (AR) was found to be an appropriate hub target in the protein-protein interaction network. Phytochemicals that inhibit breast cancer target were retrieved from the PubChem database and virtual screening was performed using PyRx against the AR protein. Thereby, the AR was found to be the target protein and 2-hydroxynaringenin was discovered to be a possible phytochemical lead molecule for combating TNBC. Moreover, the AR and the 2-hydroxynaringenin complex showed structural stability and higher binding affinity through molecular dynamics and MM-GBSA studies. AR was identified as a hub protein that is highly expressed in breast cancer and 2-hydroxynaringenin efficacy of counter TNBC requires further investigation both in vitro and in vivo.

Structural insights on the interaction potential of natural leads against major protein targets of SARS-CoV-2: Molecular modelling, docking and dynamic simulation studies

The study aimed to screen prospective molecular targets of BCC and potential natural lead candidates as effective binders by computational modeling, molecular docking, and dynamic (MD) simulation studies. Based on the virulent functions, tRNA 5-methylaminomethyl-2-thiouridine biosynthesis bifunctional protein (mnmC) and pyrimidine/purine nucleoside phosphorylase (ppnP) were selected as the prospective molecular targets. In the absence of experimental data, the three-dimensional (3D) structures of these targets were computationally predicted. After a thorough literature survey and database search, the drug-likeness, and pharmacokinetic properties of 70 natural molecules were computationally predicted and the effectual binding of the best lead molecules against both the targets was predicted by molecular docking. The stabilities of the best-docked complexes were validated by MD simulation and the binding energy calculations were carried out by MM-GBSA approaches. The present study revealed that the hypothetical models of mnmC and ppnP showed stereochemical accuracy. The study also showed that among 70 natural compounds subjected to computational screening, Honokiol (3',5-Di(prop-2-en-1-yl) [1,1'-biphenyl]-2,4'-diol) present in Magnolia showed ideal drug-likeness, pharmacokinetic features and showed effectual binding with mnmC and ppnP (binding energies -7.3kcal/mol and -6.6kcal/mol, respectively). The MD simulation and GBSA calculation studies showed that the ligand-protein complexes stabilized throughout tMD simulation. The present study suggests that Honokiol can be used as a potential lead molecule against mnmC and ppnP targets of BCC and this study provides insight into further experimental validation for alternative lead development against drug resistant BCC.

Lymphatic filariasis is a debilitating vector borne parasitic disease that infects human lymphatic system by nematode Brugia malayi. Currently available anti-filarial drugs are effective only on the larval stages of parasite. So far, no effective drugs are available for humans to treat filarial infections. In this regard, aspartate semialdehyde dehydrogenase (ASDase) in lysine biosynthetic pathway from Wolbachia endosymbiont Brugia malayi represents an attractive therapeutic target for the development of novel anti-filarial agents. In this present study, molecular modeling combined with molecular dynamics simulations and structure-based virtual screening were performed to identify potent lead molecules against ASDase. Based on Glide score, toxicity profile, binding affinity and mode of interactions with the ASDase, five potent lead molecules were selected. The molecular docking and dynamics results revealed that the amino acid residues Arg103, Asn133, Cys134, Gln161, Ser164, Lys218, Arg239, His246, and Asn321 plays a crucial role in effective binding of Top leads into the active site of ASDase. The stability of the ASDase-lead complexes was confirmed by running the 30 ns molecular dynamics simulations. The pharmacokinetic properties of the identified lead molecules are in the acceptable range. Furthermore, density functional theory and binding free energy calculations were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-filarial agents to combat the pathogenecity of Brugia malayi.

Snake venom metalloproteinase (SVMP) (Echis coloratus (Carpet viper) is a multifunctional enzyme that is involved in producing several symptoms that follow a snakebite, such as severe local hemorrhage, nervous system effects and tissue necrosis. Because the three-dimensional (3D) structure of SVMP is not known, models were constructed, and the best model was selected based on its stereo-chemical quality. The stability of the modeled protein was analyzed through molecular dynamics (MD) simulation studies. Structure-based virtual screening was performed, and 15 potential molecules with the highest binding energies were selected. Further analysis was carried out with induced fit docking, Prime/MM–GBSA (ΔGBind calculations), quantum-polarized ligand docking, and density functional theory calculations. Further, the stability of the lead molecules in the SVMP-active site was examined using MD simulation. The results showed that the selected lead molecules were highly stable in the active site of SVMP. Hence, these molecules could potentially be selective inhibitors of SVMP. These lead molecules can be experimentally validated, and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for snake antivenom.

Design, synthesis and molecular dynamic studies of novel imidazo/pyrido-pyrimidine clubbed ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate derivatives as potent anti-tubercular agents

Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (-59.6 kcal/mol) binds more strongly as compared to compound-8 (-46.3 kcal/mol) and remdesivir (-29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.

Dispersion of graphene using surfactant mixtures: Experimental and molecular dynamics simulation studies

Although cancer continues to be one of the world’s major causes of death, current cancer drugs have many serious side effects. There remains a need for new anticancer agents to overcome these shortcomings. Alternaria is one of the most widespread fungal genera, many species of which produce several classes of metabolites with potential polypharmacological activities. A few quinones and pyrones from Alternaria spp. have proven to exert cytotoxic effects against certain cancer cell lines, but their molecular mode of action is not known. The current study aimed to investigate the potential mechanisms that underlie the anticancer activity of a few selected quinones and pyrones from Alternaria solani and Alternaria alternata by molecular docking and dynamic simulation approaches. The selected metabolites were screened for their binding affinity to Heat shock protein 90 (HSP90), which is a known anticancer drug target. Molecular docking studies have revealed that Macrosporin, Altersolanol B, Fonsecin, and Neoaltenuene have good binding affinities with the target protein and the stabilities of the formed complexes were evaluated through molecular dynamics simulations. By analyzing the Root Mean Square Distance (RMSD), Root Mean Square Fluctuation (RMSF), and Principal Component Analysis (PCA) plots obtained from molecular dynamics simulations, this study shows that the complexes of all 4 lead molecules with target protein are stable over a 100 ns period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were used to compute the binding free energies. The lead molecules were studied using in-silico analysis to determine their drug-likeness based on their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and physicochemical properties. The results demonstrate that Macrosporin, Fonsecin, and Neoaltenuene could become promising anticancer molecules that target HSP90. Communicated by Ramaswamy H. Sarma